The treatment of mental depression accompanied by anxiety has been assisted in the past by administration of a variety of hetero and homo tricyclic compounds having aliphatic amino, particularly aminopropyl and aminopropylidene, substituents attached to the central ring of the tricyclic compound. Active compounds discovered to be useful in this method of treatment include the heterocyclic compounds imipramine and desipramine and the homocyclic compounds amitriptyline, nortriptyline and protriptyline. These compounds differ widely in their potencies and in the types of pharmacological properties. However, it is well known through metabolic studies that these compounds, depicted below, are subject to oxidation of the central ring structure at the 10- or 11- carbons, i.e., the ethane or ethylene bridge between the two benzene rings: ##SPC1##
Wherein ##STR1## in which R is H or CH.sub.3.
In accordance with the present invention, there is produced a class of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene compounds which have a perfluorinated ethane substituent bridging the benzene rings. This perfluoroethyl bridge is resistant to known chemical means of oxidation. This class of compounds, however, is active as antidepressants, as shown by their ability to combat the sedative effects of the reserpine derivative, tetrabenazine, in an animal model of depression. These compounds are useful in the treatment of humans affected by mental depression accompanied by anxiety and agitation, since these compounds possess tranquillizing activity in addition to their antidepressant effect. Many of the compounds presently used in treating depression have a strong excitatory or stimulatory effect on the central nervous system which can lead to undesirable anxiety and agitation in the patient being treated. In animal tests conducted on the compounds of the present invention, no strong stimulatory effect was noted.
The compounds of the present invention are depicted in the following structural formula: ##SPC2##
in which
R.sub.1 and R.sub.2 can be alike or different and are either hydrogen, alkyl, aralkyl, alkenyl, alkynyl, or can be joined together through an atom of nitrogen, oxygen or sulfur to form a heterocyclic ring of from 5-6 atoms, or a derivative thereof in which one or more of the hydrogen atoms attached to the 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9- positions is replaced by halogen, alkyl, alkoxy, perfluoroalkyl, alkylmercapto, alkylsulfonyl, and dialkylsulfamoyl. PA1 R.sub.1 and R.sub.2 are alike or different and are either hydrogen, alkyl, aralkyl, alkenyl, alkynyl, or can be joined together through an atom of nitrogen, oxygen or sulfur to form a heterocyclic ring of from 5-6 atoms, or a derivative thereof in which one or more of the hydrogen atoms attached to the 1-, 2-, 3-, 4-, 6-, 7- 8- or 9- positions is replaced by halogen, alkyl, alkoxy, perfluoroalkyl, alkylmercapto, alkylsulfonyl, and dialkylsulfamoyl. As indicated above, the aromatic rings of the above compounds are substituted optionally by replacement by one or more of the hydrogen atoms attached to the 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9- positions by halogen, especially chlorine or bromine, alkyl, preferably of from 1-6 carbon atoms, alkoxy, preferably loweralkoxy of from 1-5 carbon atoms, perfluoroalkyl, especially trifluoromethyl or pentafluoroethyl, alkylmercapto, preferably containing from 1-6 carbon atoms, alkylsulfonyl, preferably of from 1-6 carbon atoms, and dialkylsulfamoyl, preferably having from 2-8 carbon atoms.
This invention also relates to the novel processes and the novel intermediates utilized in the production of the new 10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-propylamines and the corresponding .DELTA.-5-.gamma.-propylamines, as well as the N-alkyl and the N,N-dialkyl derivative, e.g., the N-methyl or N-ethyl and the N,N-dimethyl or the N,N-diethyl derivatives thereof.
The invention further relates to antidepressant pharmaceutical formulations of the new tetrafluorodibenzo[a,d]cycloheptene-5-propylamines and the corresponding .DELTA.-5-.gamma.-propylamines and to methods of treating mental depression and particularly mental depression accompanied by anxiety or agitation, using the novel compounds and/or pharmaceutical formulations thereof described hereinafter.
A preferred group of compounds included within the scope of the present invention are compounds of the above formula in which the R.sub.1 and R.sub.2 substituents are preferably loweralkyl substituents of from 1-6 carbon atoms or hydrogen, and one to two of the ring substituent at the 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9- position is either hydrogen, halogen selected from chlorine or fluorine, loweralkyl of from 1-6 carbon atoms, loweralkoxy of from 1-5 carbon atoms, or trifluoromethyl.
An especially preferred group of compounds included within the scope of the present invention is represented by the formula ##SPC3## in which R.sub.3 and R.sub.4 substituents are each either hydrogen or loweralkyl of from 1-6 carbon atoms.
Illustrative of the compounds included within the scope of my invention are 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-propyl amine, the N-methyl derivative of 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-propyl amine, the N,N-dimethyl derivative of 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-propyl amine, 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]-cycloheptene-.DELTA. -5-.gamma.-propylamine, the N-methyl derivative of 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]-cycloheptene-.DELTA. -5-.gamma.-propylamine, and the N,N-dimethyl derivative of 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-.DELTA.- 5-.gamma.-propylamine.
Also included among the compounds useful in the method of the present invention are the N-oxides of the tertiary amines and the non-toxic pharmaceutically acceptable salts of the amines and N-oxides, the preferred salts being the non-toxic acid addition salts such as the hydrochloride, the maleate, and the like.
The compounds represented above in either the free base or salt form possess useful pharmacologic properties. In particular, they have been found to possess antidepressant and tranquillizing activity. It has been found that the administration of the compounds of the present invention depicted in the above formulae counteracts the sedative effects of the reserpine derivative, tetrabenazine, in an animal model of depression. These compounds are therefore useful in the treatment of depression in humans, particularly depression accompanied by anxiety or agitation. As antidepressant drugs, these compounds may be administered either orally or parenterally. The formulations for administration may be prepared in conventional manner, employing conventional pharmaceutical carriers and excipients.
The non-toxic acid addition salts useful as components in the compositions provided by the present invention are salts formed by the reaction of an equivalent amount of the amine compound of the above formula and an acid which is pharmacologically acceptable in the intended doses. Salts of the above compound which are useful are salts of the amine with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, acetic acid, propionic acid, lactic acid, gluconic acid, maleic acid, succinic acid, tartaric acid, and the like. Salts of these acids with the amine base are useful as the active components of the compositions in the method of this invention.
Daily doses are based on body weight of the test animal and vary between 1 and 100 mg./kg./day for mature animals. For larger animals, up to 100 kg. and above, proportional doses are employed based on the weight of the animal. For the treatment of depression in humans, therefore, a unit dosage form of from 1-25 mg./dose is satisfactory for administration on a 4-times-a-day schedule. Suitable dosage units provided for the administration of the compositions used in the method of the invention are tablets, capsules (which can be suitable formulated for either immediate or sustained release), syrups, elixirs, parenteral solutions and the like. These dosage forms preferably contain per unit one or more multiples of the desired dosage unit in combination with the pharmaceutically acceptable diluent or carrier required for preparing the dosage unit.
In treating depression in humans with antidepressants it is preferable to first administer a minimal amount of medication and then to increase the dose by one dosage unit per day until an antidepressant effect is noted. Ordinarily, the antidepressant effect is evident within 3 or 4 days but may take as long as 30 days to become evident. It is important to note that individual variation among patients with respect to the total daily dosage as well as with respect to the lag in effect requires individualization of dose to the patient being treated.
The compounds represented by the above structural formulae may be prepared as illustrated below: ##SPC4##
in which
In carrying out the process of the above invention, the critical steps are those employed in preparing intermediate ketone II, i.e., the 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-one. In preparing this ketone from the known starting material, 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-10,11-dione by reaction with a large excess of sulfur tetrafluoride in the presence of mercury and a trace of hydrogen fluoride, certain alternate reactions occur which produce fluorinated intermediates which may then be converted to the desired final product.
When the starting 10,11-dione compound is treated with sulfur tetrafluoride in the presence of mercury and hydrogen fluoride at temperatures in excess of 100.degree.C., the desired tetrafluorodibenzocycloheptenone is produced directly; thus, in a preferred method of producing the 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-one it is preferred to first mix the diketone, excess sulfur tetrafluoride, mercury, and a trace of hydrogen fluoride in a sealed vessel generally impervious to the action of hydrogen fluoride, and agitate for a period of from 1-3 hours, preferably 2 hours, at 120.degree.C., then raise the temperature for an additional 2-hour period to 140.degree.C., followed by an additional 6-hour period at 160.degree.C. The same result is accomplished by heating the mixture in an enclosed vessel over a period of 10 hours rapidly at first to 120.degree.C. and then at a slower rate until the temperature reaches 160.degree.C., which is maintained for a period of from 4-10 hours and preferably for about 6 hours. In this manner, the product 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-one is produced directly and may be purified by a combination of extraction, sublimation, and crystallization.
In an alternative method of preparing the desired tetrafluoro ketone, the starting 10,11-dihydro-5H-dibenzo[a,d]-cycloheptene-10,11-dione is converted to Compound I. The 10,11-dihydro-5,5,10,10,11,11-hexafluoro[a,d]cycloheptene is heated for a period of from 8-12 hours, preferably about 10 hours, at 80.degree.C., mixed with excess sulfur tetrafluoride, mercury, and a trace amount of hydrogen fluoride. The product produced in this manner may be isolated by extraction, sublimation, and chromatography on silica gel. The product produced in this manner is then converted to the desired 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptenone by heating with aqueous acid for a period of from 10-50 hours. In a preferred method of carrying out this conversion, a mixture of glacial acetic acid and dilute hydrochloric acid is mixed with the hexafluoro compound and alternately maintained at about 25.degree.C. for a period of 20 hours and heated at 65.degree.C. for about 3 hours. The product is obtained as a residue after concentrating the entire reaction mixture under reduced pressure. The residual crude product is partitioned between water and benzene, sublimed, and chromatographed on a column of silica gel. Selected portions of the eluate from the chromatographic column may be evaporated to produce the desired crystalline tetrafluoro ketone product.
In a still further alternate method of preparing the desired tetrafluoromethyl intermediate, the starting 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10,11-dione is heated with an excess of sulfur tetrafluoride, mercury, and a small amount of hydrogen fluoride, along with a hydrocarbon solvent, such as methylene chloride or benzene, in an enclosed reaction vessel, for a period of from 5-20 hours, preferably 10 hours, at a temperature of 80.degree.C. The product III produced in this manner is 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene, which is purified in a manner described for the other fluorinated products, i.e., extraction, sublimation, and chromatography on silica gel. The product produced in this manner may be converted to the desired tetrafluoro ketone by oxidation. A preferable method of carrying out the oxidation is to treat a mixture of the 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene and chromium trioxide in trifluoroacetic acid and glacial acetic acid at the refluxing temperature for a period of from 1-5 hours, preferably 21/4 hours. The product is extracted and purified in the manner previously described for the same material 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-one, prepared by the direct fluorination method.
The 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[ a,d]cycloheptenone intermediate is then converted to the desired 10,11-dihydro-N,N-dimethyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohep tene-.DELTA.-5-.gamma.-propylamine by known processes. Thus, the intermediate ketone is reacted with a Grignard reagent formed by the reaction of magnesium and a dialkylaminopropyl halide. The Grignard reagent and the tetrafluoro ketone are mixed while cooling until the reaction is essentially complete, and stirring allowed to continue for a period of approximately 24 hours while maintaining the temperature of about 5.degree.-10.degree.C. Th solvent employed for the reaction is generally one which is inert under the conditions, such as an ether, for example, ethyl ether or tetrahydrofuran. The Grignard addition product is then hydrolyzed under essentially neutral conditions and the bulk of the solvent is removed by evaporation under reduced pressure. The hydrolyzed product is extracted with a solvent, i.e., an aromatic hydrocarbon such as benzene, and the product obtained by evaporation of the solvent under reduced pressure leaving the product, 10,11-dihydro-5-(3-dimethylaminopropyl)-10,10,11,11-tetrafluoro-5H-dibenzo [a,d]cyclohepten-5-ol, as a residual solid.
The thus-obtained product is converted by dehydration using a strong acid under substantially anhydrous conditions; for example, heating at a temperature of from 25.degree.C. to the reflux temperature of a reaction mixture containing the 5-ol compound and a mixture of trifluoroacetic acid and trifluoroacetic anhydride to produce 10,11-dihydro-N,N-dimethyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohep tene-.DELTA.-5-.gamma.-propylamine.